Letrozole, chemically named as 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl)]-benzonitrile (I) is one of a new class of drugs, known as aromatase inhibitors, which function by reducing oestrogen levels in postmenopausal women as many breast cancers increase in size by utilising the hormone oestrogen. In women who have undergone the menopause, the main source of oestrogen is through the conversion of androgens (sex hormones produced by the adrenal glands) into oestrogen. The conversion process, which is known as aromatisation, happens mainly in the fatty tissues of the body and is catalysed by an enzyme called aromatase. Letrozole blocks this aromatisation process and reduces the amount of oestrogen in the body. Consequently, Letrozole is marketed as a type of hormonal therapy that is used in the treatment of breast cancer in women.

Letrozole and processes to prepare it were first described in U.S. Pat. No. 4,978,672. The synthesis of Letrozole proceeded via the reaction of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) with 4-fluorobenzonitrile (IV) in the presence of a catalyst, potassium tert-butoxide. The preparation of intermediate (III) was achieved by the reaction of 4-bromomethylbenzonitrile with 1,2,4-triazole in a mixture of chloroform and acetonitrile at reflux, followed by the purification of the product (III) by column chromatography. It was found that during the preparation of intermediate (III), an undesired regioisomer, namely 4-[(1-(1,3,4-triazolyl)-methyl]benzonitrile (V), was formed in about 20-25% yield. Consequently, this leads to an uneconomical loss of yield and to a difficult and inconvenient purification of intermediate (III), which was required to remove the regioisomeric impurity (V). In addition, complete purification was not possible and the impurity (V) was carried through the synthesis resulting in the formation of regioisomer (II) in the synthetic step to prepare Letrozole. As a consequence, the final purification of Letrozole had to involve the removal of impurity (II). These two purifications were very difficult and a substantial quantity of material was lost during the purifications by column chromatography. In addition, the removal of the impurities by column chromatography vastly increased the solvent consumption of the process and purification using column chromatography is not a practical approach for the industrial production of Letrozole or its intermediates.

Another process for the preparation of Letrozole, disclosed in patent application WO 2005/047269, recognised that the removal of the undesired regioisomers by column chromatography is a problem. The disclosed method for separation of the unwanted impurity (V) from the intermediate (III) is by preparation of its hydrochloride salt, which is relatively less soluble in the solvents dichloromethane and chloroform, and separation by filtration while the desired product hydrochloride salt remains in solution. The desired intermediate is then isolated as the free base and purified by removal of solvent to afford the intermediate (III) with a purity of 99.7% by HPLC. Although control of the isomeric purity was somewhat achieved by this method, the loss of significant quantities of the desired product (III) could not be avoided and this route is not attractive for commercial production, particularly as the process involved the use of several solvents and a lengthy process for the separation of the undesired isomer which makes the process less feasible for scale-up. In addition, regioisomeric impurity (V) could still be detected in the product (III) and, as described above, this is a great disadvantage in the preparation of Letrozole as impurity (V) is converted into regioisomeric impurity (II) which is very difficult to remove from Letrozole on a commercial scale.
A regio specific preparation of the intermediate 4-[(1-(1,2,4-triazolyl)methyl]-benzonitrile (III), was disclosed in patent application WO 2004/076409. The disclosed process afforded intermediate (III) significantly free from its regioisomeric impurity by using the 4-amino-derivative of 1,2,4-triazole so that regioselectivity in the reaction could be achieved. The desired intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) was obtained by de-amination of its 4-amino derivative with sodium nitrite and concentrated hydrochloric acid. However, this process suffers from the disadvantages that extra steps are involved in the synthesis and toxic nitrous acid is formed during the de-amination reaction. Consequently, it is not a very safe and feasible approach for the commercial production of Letrozole. In addition, this process, although reducing the level of 1,3,4-triazolyl isomeric impurity, did not totally eliminate the formation of the impurity.
Similar approaches to reducing the regioisomeric impurity were discussed in patent applications WO 2007/039912 and US 2007/0066831, wherein the reaction of an alkali metal (preferably sodium or potassium) salt of 1,2,4-triazole with α-bromo-tolunitrile (4-bromomethylbenzonitrile) was disclosed. The alkali metal salt of 1,2,4-triazole was dissolved in a solvent such as NMP, DMAc, DMF, THF or a mixture thereof, and subsequently treated with 4-bromomethylbenzonitrile to afford intermediate (III). This process, although reducing the level of 1,3,4-triazolyl isomeric impurity, did not totally eliminate the formation of the impurity. In addition, the formation of the alkali salt of 1,2,4-triazole also increases the time cycle of the process due to the additional step. The process also required column chromatography for purification of the final product Letrozole, which again makes this process unfeasible for industrial application.

In another approach, disclosed in patent application, WO 2007/144896, a 4,4′-disubstituted diphenylmethane moiety was prepared and then the 1,2,4-triazole ring was introduced to afford Letrozole. The process involved the coupling of 4-fluorobenzonitrile (IV) with 4-tolunitrile in DMF using potassium tertiary butoxide as a catalyst. The resulting 4,4′-di(cyanophenyl)methane was brominated with N-bromosuccinimide to afford a bromomethyl intermediate, which was reacted with 1,2,4-triazole to afford Letrozole. However, formation of the 1,3,4-triazolyl isomeric impurity (II) could not be totally avoided and, in addition, the reaction of 4-tolunitrile and 4-fluorobenzonitrile also leads to significant formation of a tris-phenyl impurity (T) which is problematic to remove, particularly on a commercial scale.
Another process, disclosed in patent application, US 2005/0209294, describes the reaction of 4-bromomethylbenzonitrile with the Li, Na or K salt of 1,2,4-triazole in tetrahydrofuran or N,N-dimethylformamide at 10° C. The product, intermediate (III), was then purified by solvent crystallization using a solvent selected from a group comprising 2-propanol, toluene or diisopropyl ether. This process required one additional step to prepare the 1,2,4-triazole Li, Na or K salt and did not give a pure product.
A further process, disclosed in patent application WO2007/090464 A1, describes the preparation of intermediate (III) by reacting 1,2,4-triazole with a suspension of sodium hydride before further reaction with 4-bromomethylbenzonitrile. The reaction product was directly converted to Letrozole without further purification. Repetition of the process disclosed in this patent application gave inconsistent regioisomeric impurity levels in Letrozole and intermediate (III), giving around 90.0% purity at best. In addition, the use of sodium hydride also makes the process relatively unsafe on a commercial scale.
A process, disclosed in patent application WO 2007/054964 A2, describes the isolation of intermediate (III) by reacting 1,2,4-triazole with 4-bromomethyl-benzonitrile in 2-propanol using potassium carbonate as base. After completion of the reaction, the undesired regioisomer (V) was removed by making the hydrochloride salt of the crude reaction mixture followed by solvent extraction and then extraction of the product under alkaline conditions. Different extractions under various pH conditions to achieve the desired purity make the process lengthy and cumbersome and repetition of the process does not lead to intermediate (III) or Letrozole (I) free from their respective regioisomeric impurities.
A process, disclosed in patent application WO2007/107733 A1, includes the use of Caesium carbonate as a base and potassium iodide in catalytic quantity in the reaction of 1,2,4-triazole with 4-bromomethylbenzonitrile. In the reaction, CsCO3, KI and 1,2,4-triazole were taken in acetone and a solution of 4-bromomethyl-benzonitrile in DCM was slowly added followed by refluxing of the reaction mixture. Isolation and purification of the desired isomer (III) was carried out by making the hydrochloride salt to afford product (III) in 99% of the desired isomeric purity.
Another process, disclosed in patent application WO 2009/069140 A1, describes the preparation of triazole intermediate (III) by addition of 1,2,4-triazole in small lots to a mixture of 4-bromomethylbenzonitrile and a base (such as sodium or potassium carbonate) in toluene at 50 to 110° C. The residue left after removal of the organic solvent was dissolved in ethyl acetate and washed with water. IPA-HCl solution was then added to adjust the pH to between 0 and 2. The purified triazole intermediate was liberated by basifying the hydrochloride salt to afford a product with 99.0% isomeric purity.
In all the acid/base purification methods discussed above, when repeated the regioisomeric purity of the desired isomer (III) or (I) was found to be 99.0% at best. The methods also required extraction with various solvents and/or column chromatography which makes the process less viable on a commercial scale.
Therefore the prior art processes described above for the preparation of Letrozole and its intermediates have major disadvantages with respect to the formation and removal of process related impurities; poor commercial viability due to the use of hazardous reactants; expensive, time consuming separation methods such as column chromatography; and/or low yields of the final product.
As the commercial production of Letrozole is of great importance and in view of the above disadvantages associated with the prior art there is a real need for alternative and improved processes for the preparation of Letrozole (I) and intermediate 4-[(1-(1,2,4-triazolyl)-methyl]benzonitrile (III) which do not involve multiple steps and further eliminate the need for cumbersome purification techniques, particularly for the removal of the regioisomers (II) and (V). The alternative processes must be economical and high yielding and provide Letrozole with a high degree of chemical purity.
The present process discloses a simple, economic and commercially viable process for the preparation of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) and Letrozole (I) with 99.7% or more isomeric and chemical purity.